Objectives Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).
Methods Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.
Results In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68).
Conclusions CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.
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Contributors Study conception and design: PS, MO; acquisition and analysis of data: PS, FV, LF, EF, PO, SR, SA-S, AD, JD-S, KF, KF, HF, AG, HJ, JK, JK, BL, ML, EP, JP, AR, MLS, AS, HT, CAFA, JW, PW, ACL, DYH, MO; writing of the manuscript: PS, SR, DYH, MO; critical revision of the manuscript: PS, FV, LF, EF, PO, SR, SA-S, AD, JD-S, KF, KF, HF, AG, HJ, JK, JK, BL, ML, EP, JP, AR, MLS, AS, HT, CAFA, JW, PW, ACL, DYH, MO.
Funding This study was supported by the EU Joint Programme – Neurodegenerative Diseases (JPND) research networks SOPHIA (01ED1202A), BiomarkAPD(01ED1203F) and Prefrontals (01ED1512), the German Federal Ministry of Education and Research (FTLDc O1GI1007A, KKNMS, MND-Net01GM1103A), the EU (NADINE 246513, FAIR-PARK II 633190), the foundation of the state Baden-Württemberg (D.3830), Thierry Latran foundation, and Boehringer Ingelheim Ulm University BioCenter(D.5009).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Local ethics committees (Ulm and Göttingen).
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators FTLDc study group: Nibal Ackl (LMU München), Sönke Arlt (Hamburg), Franziska Albrecht (Leipzig), Sandrine Bisenius (Leipzig), Svenja Gehlhaar (Hamburg), Jakob Gleiss (Hamburg), Theresa Halder (LMU München), Jan Lehmbeck (Hamburg), Leonie Lampe (Leipzig), Johannes Levin (LMU München), Manuel Maler (Erlangen), Felix Oberhauser (Hamburg), Timo Oberstein (Erlangen), Catharina Prix (LMU München), Theresa Raiser (LMU München), Tanja Richter!Schmiedinger (Erlangen), Dorothee Saur (Leipzig), Lisa Schachner (Erlangen), Sonja Schönecker (LMU München), Katharina Schuemberg (Leipzig), Gisela Stenglein Krapf (LMU München), Elisabeth Wlasich (LMU München).
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